Electrochemical sensor system

ABSTRACT

An electrochemical sensor system comprises an electrochemical sensor and a hydrogel composition. The electrochemical sensor has at least a counter electrode and a working electrode. The hydrogel composition contacts the working electrode. The hydrogel composition comprises a first monomer, a second monomer, a cross-linking agent, and a solvent. The first monomer has hydrophilic characteristics. The second monomer has hydrophobic characteristics. The ratio of the first monomer to the second monomer is from about 0.1:99.9 to about 99.9:0.1.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. patent application Ser. No.11/666,270, filed Feb. 19, 2008, which is: a national stage ofApplication No. PCT/US2005/038966 filed Oct. 27, 2005, is a continuationof U.S. patent application Ser. No. 11/201,334, filed Aug. 11, 2005, isa continuation of U.S. patent application Ser. No. 10/974,963, filedOct. 28, 2004, and claims priority from Provisional Application No.60/717,064 filed Sep. 14, 2005; and Provisional Application No.60/676,453 filed Apr. 29, 2005.

FIELD OF THE INVENTION

The present invention generally relates to hydrogel compositions. Thehydrogel composition in one application is adapted to be used in atransdermal method of determining the concentration of an analyte (e.g.,glucose).

BACKGROUND OF THE INVENTION

The quantitative determination of analytes in body fluids is of greatimportance in the diagnoses and maintenance of certain physiologicalabnormalities. For example, lactate, cholesterol and bilirubin should bemonitored in certain individuals. In particular, it is important thatdiabetic individuals frequently check the glucose level in their bodyfluids to regulate the glucose intake in their diets. The results ofsuch tests can be used to determine what, if any, insulin or othermedication needs to be administered.

In some existing techniques, a lancet may be used to draw fluid (e.g.,blood) from a user. This fluid is then used with an instrument or meterto determine an analyte concentration. It would be desirable toeliminate the need to use a lancet, while still accurately determiningthe analyte concentration.

One non-invasive method for obtaining a sample without using a lancet isto use a transdermal sample of analytes found in interstitial fluid(ISF). In this method, a composition is placed on the skin and assistsin facilitating the extraction of the ISF from the user skin's to asensing instrument or meter. This composition needs to possesssufficient mechanical and thermal stability to provide a relativelystatic, reactive and aqueous conduct between the dermal sampling siteand sensing instrument. It would be desirable to find such a compositionthat contains such attributes and is adapted to be used in transdermalsampling.

SUMMARY OF THE INVENTION

According to one embodiment, a hydrogel composition comprises a firstmonomer, a second monomer, a cross-linking agent, and a solvent. Thefirst monomer is selected from Formula I:

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or the combination of Rand R1 is selected from 1 carbon to 5 carbon atoms such that a 3-7member heterocyclic moiety is formed.

The second monomer is selected from the group consisting of Formula IIand Formula III, wherein Formula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, (C₃-C₇)cycloalkyl or aromatic moieties. The alkyl is optionally substitutedwith one or more substituents selected from halos, haloalkyls,cycloalkyls, nitros, cyanos, 4-8 member heterocyclic moieties. Theheterocyclic moieties are optionally substituted with one or morealkyls, halos, haloalkyls, cycloalkyls, nitros, and cyanos. Thecycloalkyl is optionally substituted with one or more substituentsselected from alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos. The aromatic moieties are optionally substituted with one ormore substituents selected from alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos. If R3 is H or CH₃, then R4 is a (C₃-C₁₈)alkyl, a(C₃-C₇)cycloalkyl or an aromatic moiety. The alkyl, cycloalkyl oraromatic moiety is optionally substituted with one or more substituents.If R4 is H or CH₃, then R3 is a (C₃-C₁₈)alkyl, a (C₃-C₇)cycloalkyl or anaromatic moiety. The alkyl, cycloalkyl or aromatic moiety is optionallysubstituted with one or more substituents.

Formula III is

wherein

R5 is selected from (C₃-C₁₈)alkyl, (C₃-C₇) cycloalkyl or aromaticmoieties. The alkyl is optionally substituted with one or moresubstituents selected from halos, haloalkyls, cycloalkyls, nitros,cyanos, 4-8 member heterocyclic moieties. The heterocyclic moieties areoptionally substituted with one or more alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos. The cycloalkyl is optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos. The aromatic moieties areoptionally substituted with one or more substituents selected fromalkyls, halos, haloalkyls, cycloalkyls, nitros, and cyanos. The ratio ofthe first monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1.

According to one embodiment, an electrochemical sensor system comprisesan electrochemical sensor and a hydrogel composition. Theelectrochemical sensor has at least a counter electrode and a workingelectrode. The hydrogel composition contacts the working electrode. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer is selected fromhydroxy alkyl methacrylates, acrylamide, N,N di-alkyl acrylamides,methacrylic acid, acrylic acid, methacrylate metal salts, acrylate metalsalts, iticonic acid, maleic acid, methacrylamide,N,N-dialkylacrylamide, styrene sulfonic acid, styrene sulfonate metalsalts, styrene carboxylic acid, styrene carboxylate metal salts,acrylamido-2-methylpropane sulfonic acid, acrylamido-2-methylpropanesulfonate metal salts, 2-vinyl N-alkylpyridinium halide, 4-vinylN-alkylpyridinium halide, or Formula I, which is discussed above. Thesecond monomer is selected from the group consisting of alkyl(meth)acrylates, Formula II, Formula III, and Formula IV, in whichFormula II and Formula III are discussed above.

Formula IV is

whereinR2 is selected from (C₁-C₁₈)alkyl, (C₃-C₇)cycloalkyl and aromaticmoieties. The alkyl is optionally substituted with one or moresubstituents selected from halos, haloalkyls, cycloalkyls, nitros,cyanos, 4-8 member heterocyclic moieties. The heterocyclic moieties areoptionally substituted with one or more alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos. The cycloalkyl is optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos. The aromatic moieties areoptionally substituted with one or more substituents selected fromalkyls, halos, haloalkyls, cycloalkyls, nitros, and cyanos. The ratio ofthe first monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1.

According to one embodiment, an electrochemical sensor system comprisesan electrochemical sensor and a hydrogel composition. Theelectrochemical sensor has at least a counter electrode and a workingelectrode. The hydrogel composition contacts the working electrode. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer is selected fromFormula I, which is discussed above. The second monomer is selected fromthe group consisting of alkyl (meth)acrylates, Formula II, Formula III,and Formula IV, which are discussed above.

According to a further embodiment, an electrochemical sensor systemcomprises an electrochemical sensor and a hydrogel composition. Theelectrochemical sensor has at least a counter electrode and a workingelectrode. The hydrogel composition contacts the working electrode. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer is selected fromthe group consisting of N-vinyl pyrrolidone, hydroxy alkylmethacrylates, acrylamide, and N,N di-alkyl acrylamides. The secondmonomer is selected from the group consisting of alkyl (meth)acrylates,N-vinyl acrylamide, vinyl esters, and vinyl ethers. The ratio of thefirst monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1.

According to yet another embodiment, an electrochemical sensor systemcomprises an electrochemical sensor and a hydrogel composition. Theelectrochemical sensor has at least a counter electrode and a workingelectrode. The hydrogel composition contacts the working electrode. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer has hydrophiliccharacteristics. The second monomer has hydrophobic characteristics. Theratio of the first monomer to the second monomer is from about 0.1:99.9to about 99.9:0.1.

According to one method, an analyte concentration is determined byplacing a hydrogel composition on skin. The hydrogel compositioncomprises a first monomer, a second monomer, a cross-linking agent, anda solvent. The first monomer is selected from hydroxy alkylmethacrylates, acrylamide, N,N di-alkyl acrylamides, methacrylic acid,acrylic acid, methacrylate metal salts, acrylate metal salts, iticonicacid, maleic acid, methacrylamide, N,N-dialkylacrylamide, styrenesulfonic acid, styrene sulfonate metal salts, styrene carboxylic acid,styrene carboxylate metal salts, acrylamido-2-methylpropane sulfonicacid, acrylamido-2-methylpropane sulfonate metal salts, 2-vinylN-alkylpyridinium halide, 4-vinyl N-alkylpyridinium halide, or FormulaI, which is discussed above. The second monomer is selected from thegroup consisting of alkyl (meth)acrylates, Formula II, Formula III, andFormula IV, which are discussed above. A sensor is provided and thehydrogel composition is located generally between and coupling the skinand the sensor. The interstitial fluid is sampled to determine theanalyte concentration using the sensor.

According to another method, an analyte concentration is determined. Themethod comprises placing a hydrogel composition on skin. The hydrogelcomposition comprises a first monomer, a second monomer, a cross-linkingagent, and a solvent. The first monomer is selected from Formula I,which is discussed above. The second monomer is selected from the groupconsisting of alkyl (meth)acrylates, Formula II, Formula III, andFormula IV, which are discussed above. A sensor is provided and thehydrogel composition is located generally between and coupling the skinand the sensor. The interstitial fluid is sampled to determine theanalyte concentration using the sensor.

According to a further method, an analyte concentration is determined.The method comprises placing a hydrogel composition on skin. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer is selected fromthe group consisting of N-vinyl pyrrolidone, hydroxy alkylmethacrylates, acrylamide, and N,N di-alkyl acrylamides. The secondmonomer is selected from the group consisting of alkyl (meth)acrylates,N-vinyl acylamide, vinyl esters, and vinyl ethers. The ratio of thefirst monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1. A sensor is provided and the hydrogel composition is locatedgenerally between and coupling the skin and the sensor. The interstitialfluid is sampled to determine the analyte concentration.

According to a yet another method, an analyte concentration isdetermined. The method comprises placing a hydrogel composition on skin.The hydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent. The first monomer has hydrophiliccharacteristics. The second monomer has hydrophobic characteristics. Theratio of the first monomer to the second monomer is from about 0.1:99.9to about 99.9:0.1. A sensor is provided and the hydrogel composition islocated generally between and coupling the skin and the sensor. Theinterstitial fluid is sampled to determine the analyte concentrationusing the sensor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a dried hydrogel and a mechanical support according to oneembodiment.

FIG. 2 is an electrochemical sensor according to one embodiment.

FIG. 3 is an electrochemical sensor system including the electrochemicalsensor of FIG. 2.

FIG. 4a is a graph plotting current, glucose concentration versus time.

FIG. 4b is the graph of FIG. 4a plotting current, glucose concentrationversus time that has been normalized.

FIG. 5 is a graph plotting current, glucose concentration versus time.

DETAILED DESCRIPTION OF ILLUSTRATED EMBODIMENTS

The present invention is directed to novel hydrogel compositions. Thehydrogel composition comprises a first monomer, a second monomer, across-linking agent, and a solvent (e.g., water). The hydrogelcomposition is a random, copolymeric network that combines at least thefirst and second monomer in the form of polymeric chains. Thecopolymeric network is controlled to at least some extent by thevolumetric percentages of the first and second monomers.

The terms identified below have the following meaning throughout:

The term “alkyl” mean linear or branched saturated carbon groups. Theterms “(C₁-C₃)alkyl”, “(C₁-C₁₈)alkyl” and “(C₃-C₁₈)alkyl” mean linear orbranched saturated carbon groups having from 1 to about 3 carbon atoms,1 to about 18 carbon atoms, or from about 3 to about 18 carbon atoms,respectively. Such groups include but are not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and thelike.

The term “optionally substituted” means that, unless indicatedotherwise, the moiety so modified may have one or more substituentsindicated. Each substituent may replace any H atom on the moiety somodified as long as the replacement is chemically possible andchemically stable. For example, a chemically unstable compound would beone where each of two substituents is bonded to a single C atom througheach substituent's heteratom. Another example of a chemically unstablecompound would be one where an alkoxy group is bonded to the unsaturatedcarbon of an alkene to form an enol ether. When there are twosubstituents on any moiety, each substituent is chosen independently ofthe other substituent so that, accordingly, the substituents can be thesame or different.

The term “cycloalkyl” means a saturated monocyclic alkyl group. The term“(C₃-C₇)cycloalkyl” means a saturated monocyclic alkyl group of fromabout 3 to about 7 carbon atoms. Such groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

The term “(C₃-C₆)dihydroxy alkyl” means an alkyl group, as describedabove, that includes two hydroxy (—OH) constituents bonded to asaturated carbon. The (C₃-C₆)dihydroxy alkyls may be straight orbranched. The hydroxy constituents of the (C₃-C₆)dihydroxy alkyls aretypically adjacent to each other. The (C₃-C₆)dihydroxy constituents,however, may be added at any available carbon. Such (C₃-C₆)dihydroxyalkyls include, but are not limited, to 2,3-dihydroxypropyl,3,4-dihydroxybutyl, 5,6-dihydroxyhexyl, and the like.

The term “(C₂-C₆)hydroxy alkyl” means an alkyl group, as describedabove, that includes one hydroxy (—OH) constituent bonded to a saturatedcarbon. The (C₂-C₆)hydroxy alkyls may be straight or branched. Thehydroxy constituent of the (C₂-C₆)hydroxy alkyls may be located at anyavailable carbon. Such (C₂-C₆)hydroxy alkyls include, but are notlimited, to 2-hydroxyethyl, 3-hydroxypropyl and the like.

The term “halo” means an atom selected from Cl, Br, and F.

The term “haloalkyl” means an alkyl group, as described above, thatincludes one or more halo constituent bonded to a saturated carbon. Thehaloalkyls may be straight or branched. The halo constituent of thehaloalkyls may be located at any available carbon. Such haloalkylsinclude, but are not limited, to 2-chloroethyl, 3-bromopropyl,2,2,3,3,3-pentafluoropropyl and the like.

The term “nitro” means an atom selected from —NO₂, cyano (—CN), —NHCH₃and —NHC₂H₅.

The term “heterocyclic moiety” is a substance that contains a ringstructure in which atoms other than carbon (e.g., sulfur, oxygen ornitrogen) are formed as part of the ring. For example, a 3-7 memberheterocyclic moiety includes at least one other atom other than carbonformed as a part of the ring or backbone of a 3-7 ring structure. A 4-8member heterocyclic moiety includes at least one other atom other thancarbon formed as a part of the ring or backbone of a 4-8 ring structure.

The term “hydrophilic characteristics” means having an affinity forwater or other polar solvents; readily absorbing or dissolving in wateror other polar solvents.

The term “hydrophobic characteristics” means not having an affinity forwater or other polar solvents; not readily absorbing or dissolving inwater or other polar solvents.

The term “aromatic moiety” means a substance containing one or morebenzene rings. An aromatic substituent may be monocyclic, bicyclic ortricyclic. Non-limiting examples of aromatic substituents includephenyl, benzyl, naphthyl, anthracenyl and the like.

Notations such as “(meth)acrylic acid” are used herein to denoteoptional methyl substitution. Thus, for example, “(meth)acrylic acid”includes methylacrylic acid and acrylic acid.

As discussed above, the hydrogel compositions include a first monomerand a second monomer. One embodiment of a first monomer is directed to acompound of Formula I, which is a N-vinyl acylamide.

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed.

One non-limiting example of Formula I in which R is CH₃ and R1 is H isN-vinyl acetamide. Other examples of Formula I include R being CH₂CH₃and R1 being H, which is N-vinyl propionamide.

Non-limiting examples of cyclic structures of Formula I include N-vinylpyrrolidone, which is a 5 member heterocyclic compound that includes 4carbons and 1 nitrogen in its backbone. N-vinyl pyrrolidone is shown asCompound A below:

Another example of a cyclic structure of Formula I is N-vinylcaprolactam.

It is desirable for Formula I to have hydrophilic characteristics. R andR1 are desirably independently selected such that Formula I hashydrophilic characteristics. The combination of R and R1 is alsodesirably selected to form a cyclic structure of Formula I that hashydrophilic characteristics.

In one embodiment, a first monomer of Formula I and a second monomer ofFormula II (which is discussed below), a cross-linking agent and asolvent form a hydrogel composition. The ratio of the first monomer tothe second monomer is from about 0.1:99.9 to about 99.9:0.1. Morespecifically, the ratio of the first monomer to the second monomer isfrom about 20:80 to about 80:20 and, even more specifically from about40:60 to about 60:40. One embodiment of a second monomer is directed toa compound of Formula II, which is a N-vinyl acylamide.

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents.

Examples of Formula II wherein R3 or R4 is a (C₃-C₁₈)alkyl and whereinthe alkyl is optionally substituted with one or more substituents,include, but are not limited to, N-vinyl butyramide, N-vinyl valeramide,N-vinyl lauramide, N-vinyl 4-chlorobutyramide and the like.

Examples of Formula II wherein R3 or R4 is a (C₃-C₇)cycloalkyl andwherein the cycloalkyl is optionally substituted with one or moresubstituents, include, but are not limited to, N-vinylcyclohexylcarboxamide, N-vinyl cyclopentylcarboamide, N-vinyl4-bromocyclohexylcarboxamide and the like.

Examples of Formula II wherein R3 or R4 is an aromatic moiety andwherein the aromatic moiety is optionally substituted with one or moresubstituents, include, but are not limited to, N-vinyl benzamide,N-vinyl 4-nitrobenzamide, N-vinyl naphthamide and the like.

It is desirable for Formula II to have hydrophobic characteristics. R3and R4 are desirably independently selected such that Formula II hashydrophobic characteristics.

In another embodiment, a first monomer of Formula I and a second monomerof Formula III (which is discussed below), a cross-linking agent and asolvent form a hydrogel composition. Another embodiment of a secondmonomer is directed to a compound of Formula III, which is a vinylether.

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos.

Examples of Formula III wherein R5 is a (C₃-C₁₈)alkyl and wherein thealkyl is optionally substituted with one or more substituents, include,but are not limited to, vinyl propyl ether, vinyl hexyl ether, vinyldodecyl ether, vinyl 4-chlorobutyl ether and the like.

Examples of Formula III wherein R5 is a (C₃-C₇)cycloalkyl and whereinthe cycloalkyl is optionally substituted with one or more substituents,include, but are not limited to, vinyl cyclohexyl ether, vinylcyclopentyl ether, vinyl 4-bromocyclohexyl ether and the like.

Examples of Formula III wherein R5 is an aromatic moiety and wherein thearomatic moiety is optionally substituted with one or more substituents,include, but are not limited to, vinyl phenyl ether, vinyl 4-nitrophenylether, vinyl 2-naphthyl ether and the like.

When the first and second monomers are mixed with a solvent (e.g.,water), the structural integrity of the materials may not be as strongas desired. This especially may be the situation if the first and secondmonomers are mixed with a large amount of solvent. To further increasethe mechanical strength, a cross-linking agent is added to the firstmonomer and the second monomer.

Non-limiting examples of cross-linking agents that may be used include,but are not limited to, the following: multifunctional vinyl ethers,divinylbenzenes, multifunctional acrylates, and multifunctionalacrylamides. To be a desirable cross-linking agent with the first andsecond monomers, the cross-linking agent must be of a geometry that canconnect the two polymer chains.

According to one embodiment, a cross-linking compound of Formula V(multifunctional vinyl ether) may be used.

wherein “x” is from 0 to about 4. In Formula V, the “x” assists indetermining properties of the cross-linking compound. Specifically, thegreater the “x” component of Formula V, the better elasticity and tearstrength of Formula V. By improving the elasticity and tear strength,the amount of solvent added to form the hydrogel can be greater.

An example of a multifunctional vinyl ether that may be used as across-linking agent is diethylene glycol divinyl ether acrylate, whichis shown as Compound B below.

It is contemplated that other multifunctional vinyl ethers may be usedas a cross-linking agent such as triethylene glycol divinyl ether, andtetra(ethylene glycol) divinyl ether.

According to another embodiment, a cross-linking compound of Formula VI(divinylbenzene) may be used.

wherein R6 is selected from CH₂, O, or CH₂—CH₂.

An example of a multifunctional acrylate to be used as a cross-linkingagent is ethylene glycol dimethacrylate (EGDMA), which is shown asCompound C below.

It is contemplated that other multifunctional acrylates may be used as across-linking agent such as polyethylene glycol diacrylates, diethyleneglycol dimethacrylate, diethylene glycol diacrylate, ethylene glycoldiacrylate, and 1,3-dihydroxypropyldimethacrylate.

An example of a multifunctional acrylamide that may be used as across-linking agent is N,N′ methylene biaacrylamide, which is shown asCompound D below.

It is contemplated that other multifunctional acrylamides may be used asa cross-linking agent.

The copolymeric network composition generally comprises from about 0.01to about 10 vol. % cross-linking agent. The copolymeric networkcomposition is defined herein as including the first monomer, the secondmonomer, the cross-linking agent, and other components to be discussedbelow prior to curing. The copolymeric network composition as defineddoes not include the solvent (e.g., water). More specifically, thepolymeric network composition comprises from about 0.1 to about 1 vol. %cross-linking agent.

To assist in the polymerization, a photo-initiator may be added to thefirst monomer, the second monomer and the cross-linking agent. Oneexample of a photo-initiator is2-Hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone marketed asIrgacure® 2959 by Ciba Specialty Chemicals Pty, Ltd. It is contemplatedthat other photo-initiators may be added. The polymeric networkcomposition generally comprises from 0.0001 to about 5 wt. %photo-initiator.

The first and second monomers are mixed with a solvent. One example of asolvent that is typically used is water. Another example of a solvent isa water mixture. It is contemplated that other solvents may be used inthe present invention. The amount of water may vary and is largelydependent on the amount of the first monomers and second monomerspresent in the hydrogel composition. It is contemplated that othermaterials may be added to the hydrogel composition of the first monomer,second monomer, cross-linking agent, and the solvent.

After the cross-linking agent has been added, the first and secondmonomers form a cross-linked, copolymer network. To achievepolymerization of the first and second monomers with the cross-linkingagent, the polymerization may be initiated by methods such as, forexample, ultraviolet (UV radiation with the addition of an UVinitiator), thermal initiation (with the addition of a thermalinitiator), γ-ray, and electron beam. To assist in the polymerization, aphoto-initiator may be added to the first monomer, second monomer andthe cross-linking agent. The copolymeric network in one method is soakedin a solvent (e.g., water) to create a hydrogel composition.

In one embodiment, the hydrogel composition may be adapted to serve asan interface between skin and a sensor (e.g., an electrochemicalsensor). In one method, the sensor determines the concentration of thedesired analyte in the ISF (interstitial fluid) using the hydrogelcomposition. Analytes that may be measured include glucose, lipidprofiles (e.g., cholesterol, triglycerides, LDL and HDL), microalbumin,hemoglobin A_(1C), fructose, lactate, or bilirubin. It is contemplatedthat other analyte concentrations may be determined. As used within thisapplication, the term “concentration” refers to an analyteconcentration, activity (e.g., enzymes and electrolytes), titers (e.g.,antibodies), or any other measure concentration used to measure thedesired analyte.

The hydrogel composition, which is to be used as an interface betweenskin and a sensor in this embodiment, comprises a first monomer, asecond monomer, a cross-linking agent, and a solvent (e.g., water). Thehydrogel composition is a random, copolymeric network that combines atleast the first and second monomer in the form of polymeric chains. Thecopolymeric network is controlled to at least some extent by thevolumetric percentages of the first and second monomers. In thisapplication, it is advantageous for the hydrogel composition to have abalance between gel strength and flexibility. It is also desirable forthe hydrogel composition to have a desirable signal strength.

The first monomer is adapted to provide a hydrophilic character to thehydrogel composition. The first monomer includes the compounds ofFormula I (N-vinyl acylamide), which is discussed in more detail above.

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed.

It is contemplated that other first monomers may be used includinghydroxy alkyl methacrylates, acrylamide, N,N di-alkyl acrylamides,methacrylic acid, acrylic acid, methacrylate metal salts, acrylate metalsalts, iticonic acid, maleic acid, methacrylamide,N,N-dialkylacrylamide, styrene sulfonic acid, styrene sulfonate metalsalts, styrene carboxylic acid, styrene carboxylate metal salts,acrylamido-2-methylpropane sulfonic acid, acrylamido-2-methylpropanesulfonate metal salts, 2-vinyl N-alkylpyridinium halide, or 4-vinylN-alkylpyridinium halide.

An example of a hydroxy alkyl methacrylate that may be used as a firstmonomer is hydroxy ethyl methacrylate, which is shown as Compound Ebelow.

It is contemplated that other hydroxy alkyl methacrylates may be used asthe first monomer such as hydroxy propyl methacrylate,hydroxyethylacrylate, 2,3-dihydroxypropylmethacrylate, and2,3-dihydroxypropylacrylate.

Acrylamide, which may be used as the first monomer, is shown as CompoundF below.

An example of a N,N di-alkyl acrylamide that may be used as a firstmonomer is N,N di-methyl acrylamide, which is shown as Compound G below.

It is contemplated that other N,N di-alkyl acrylamides may be used asthe first monomer such as N,N di n-propylacrylamide, N-isopropylacrylamide, and N,N-dimethylmethacrylamide.

According to another embodiment, the first monomer may be methacrylicacid, which is shown as Compound H below:

The second monomer is adapted to provide mechanical strength to thehydrogel composition. The second monomer is adapted to also provide ahydrophobic character to the hydrogel composition. By providing ahydrophobic character to the hydrogel composition, the amount of solvent(e.g., water) is better controlled.

In one embodiment, a second monomer is directed to a compound of FormulaII (N-vinyl acylamide), which is discussed in more detail above.

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents.

In another embodiment, a second monomer is directed to a compound ofFormula III (vinyl ether), which is discussed in more detail above.

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos.

A further embodiment of a second monomer is directed to a compound ofFormula IV, which is a vinyl ester.

whereinR2 is selected from (C₁-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos.

Examples of Formula IV wherein R2 is a (C₁-C₁₈)alkyl and wherein thealkyl is optionally substituted with one or more substituents, include,but are not limited to, 2-chloroethyl, 3-bromopropyl,2,2,3,3,3-pentafluoropropyl and the like.

Examples of Formula IV wherein R2 is a (C₃-C₇)cycloalkyl and wherein thecycloalkyl is optionally substituted with one or more substituents,include, but are not limited to, cyclopentyl, cyclohexyl,2-chlorocyclohexyl, 4-bromocyclohexyl and the like.

Examples of Formula IV wherein R2 is an aromatic moiety and wherein thearomatic moiety is optionally substituted with one or more substituents,include, but are not limited to, vinyl benzoate, vinyl phenylacetate,vinyl 4-bromobenzoate, vinyl 4-nitrobenzoate, vinyl 1-naphthanoate,vinyl 2-naphthanoate and the like.

Vinyl esters, such as vinyl acetate or vinyl laurate, may be used as asecond monomer. Vinyl acetate is shown below as Compound J, while vinyllaurate is shown as Compound K.

It is contemplated that other vinyl esters may be used as the secondmonomer such as vinyl propionate and vinyl butyrate. It is desirable forFormula IV to have hydrophobic characteristics. R2 is desirably selectedsuch that Formula IV has hydrophobic characteristics.

In addition to the second monomers being formed from Formulas II-IV, itis contemplated that the second monomer may further include, but is notlimited to, alkyl (meth)acrylates, which includes alkyl methacrylatesand alkyl acrylates. An example of an alkyl methacrylate that may beused as a second monomer is methyl methacrylate, which is shown asCompound L below.

It is contemplated that other alkyl methacrylates may be used as thesecond monomer such as ethyl methacrylate, propyl methacrylate, butylmethacrylate, pentyl methacrylate, hexyl methacrylate, heptylmethacrylate, octyl methacrylate, 2-ethylhexyl methacrylate, nonylmethacrylate, decyl methacrylate, undecyl methacrylate, and dodecylmethacrylate.

The ratio of the first monomer to the second monomer is from about0.1:99.9 to about 99.9:0.1. More specifically, the ratio of the firstmonomer to the second monomer is from about 80:20 to about 20:80 and,even more specifically from about 60:40 to about 40:60.

One example of a copolymer network using a first monomer and a secondmonomer is shown below in Formula M:

The first monomer used in Formula M is N-vinyl pyrrolidone and thesecond monomer used in Formula M is vinyl acetate. The “n” and m″ inFormula M represent potential repeat monomer units, in which “n” and “m”are greater than or equal to 1. The “n” and “m” of Formula M aredependent on the ratio of the first monomer to the second monomerpresent. It is contemplated that other combinations of the firstmonomers and second monomers disclosed above may be used in forminghydrogel compositions.

The copolymeric network composition generally comprises from about 0.01to about 10 vol. % cross-linking agent. As discussed above, thecopolymeric network composition is defined herein as including the firstmonomer, the second monomer, the cross-linking agent, and othercomponents to be discussed below prior to curing. The copolymericnetwork composition as defined does not include the solvent (e.g.,water). More specifically, the polymeric network composition comprisesfrom about 0.1 to about 1 vol. % cross-linking agent.

As discussed above, to assist in the polymerization, a photo-initiatormay be added to the first monomer, the second monomer and thecross-linking agent. One example of a photo-initiator is2-Hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone marketed asIrgacure® 2959 by Ciba Specialty Chemicals Pty, Ltd. It is contemplatedthat other photo-initiators may be added.

The first and second monomers are mixed with a solvent. One example of asolvent that is typically used is water. Another example of a solvent isa water mixture. It is contemplated that other solvents may be used inthe present invention. In applications that determine analyteconcentration, however, the solvent needs to be substantiallybiocompatible with the skin. The amount of water may vary and is largelydependent on the amount of the first polymers and second polymerspresent in the hydrogel composition.

It is contemplated that other materials may be added to the hydrogelcomposition of the first monomer, second monomer, cross-linking agent,and the solvent. For example, an electrolyte may be added to thehydrogel composition. Depending on the application of the hydrogelcomposition, the electrolyte may perform multiple functions. First, theelectrolyte is a chemical compound that ionizes when dissolved toproduce an electrically-conductive medium. Second, the electrolytedesirables contains a high salt concentration that when used inapplications contacting the skin assists in exerting osmotic pressure onthe skin. By exerting osmotic pressure on the skin, the electrolyteassists in driving out the interstitial fluid (ISF) that contains theanalyte. Non-limiting examples of electrolytes that may be used includesodium and potassium salts of chloride, phosphate, citrate, acetate andlactate.

The solution may further include an enzyme to assist in determining theanalyte concentration. Depending on the analyte, an enzyme may assist inconverting the analyte into a species amenable to detection, such aselectrochemical detection. One example of an enzyme that may be used indetermining glucose is glucose oxidase. It is contemplated that otherenzymes may be used such as glucose dehydrogenase. If other analytes areof interest, an appropriately selected enzyme may assist in determiningthe concentration of that analyte. The enzyme, if used, is typicallyadded after curing of the first monomer and the second monomer. Thecuring of the first and second monomers typically involves using thermalstress or applying electromagnetic radiation, which may have a negativeeffect on the activity of the enzyme. It is contemplated, however, thatthe enzyme may be mixed with the first and second monomers prior tocuring.

The solution may further include a permeation enhancer. Permeationenhancers are desirable in applications in which the hydrogelcomposition is applied to the skin. The permeation enhancer assists inopening up the pores of the skin. Non-limiting examples of permeationenhancers that may be used include, but are not limited to, squalene,unsaturated fatty acids, glycerol derivatives of fatty alcohols,dimethylsulfoxide, and alkyl esters of fatty acids.

Other materials that may be added to the hydrogel composition includebiocides, humectants, surfactants, and combinations thereof. Biocidesassist in exhibiting bacterial growth. Non-limiting examples of biocidesthat may be used include the Paraben series of preservatives, sodiumbenzoate, benzalkonium chloride, and trialkyl amines.

Humectants assist in applications in which it is desirable to keep theskin moist. Non-limiting examples of humectants that may be used includeglycerol, hexylene glycol and sorbitol, maltitol, polydextrose,propylene glycol, lactic acid, and lactate metal salts. Surfactantsassists in coupling the hydrogel composition with the skin to obtain animproved contact therebetween. Non-limiting examples of surfactants thatmay be used include alkyl phenols such as TRITON® X-100 (octyl phenolethoxylate having a molecular formula of C₁₄H₂₂O(C₂H₄O)_(n), in which anaverage “n” is 9 or 10), and sorbitol and sorbitol derivatives such asthe TWEEN™ series.

If used in an electrochemical application, the hydrogel composition maybe dried on the electrode surface and reconstituted prior to its use.When reconstituting, a solvent to be added may include an electrolyte.

In an electrochemical application, the hydrogel composition generallyhas a thickness of from about 0.1 mil to about 100 mils and, morespecifically, has a thickness of from about 1 mil to about 30 mils. Thesurface area of the electrochemical sensor covered by the hydrogelcomposition in one embodiment is from about 0.1 to about 100 cm².

The hydrogel composition possesses sufficient mechanical and thermalstability to provide a relatively static, reactive, and aqueous conduitbetween the dermal sampling site and the sensor. More specifically, itis desirable for the hydrogel composition to have physical uniformityand flexibility, and mechanical stability against shear force. Inselected applications, it may be desirable for the hydrogel compositionto maintain a water content of from about 50 to about 90 wt. % for adesired duration (e.g., from about 24 to about 72 or more hours).

In addition, the hydrogel composition possesses high hydrophilicity toresist dehydration during extended use. By reducing or substantiallyeliminating dehydration, the transport properties of the hydrogelcomposition are not altered. It is also desirable for the hydrogelcomposition to maintain the porosity of the skin. The hydrogelcomposition also desirably displays a relatively high degree ofcompressibility to assist in securing good skin/sensor connectivity orskin adhesiveness.

It is also desirable for the hydrogel composition to have porosity largeenough for enzyme entrapment. For example, in some applicationsinvolving the determination of glucose concentration, it is desirablefor the hydrogel composition to provide a matrix for glucose oxidase(GO) and a diffusion passage for glucose and hydrogen peroxide.

After the cross-linking agent has been added, the first and secondmonomers form a cross-linked, copolymer network. To achievepolymerization of the first and second monomers with the cross-linkingagent, the polymerization may be initiated by methods such as, forexample, ultraviolet (UV) radiation (e.g., high-intensity UV radiation),thermal initiation (e.g., freeze-thaw cycling), γ-ray, and electronbeam. To assist in the polymerization, a photo-initiator may be added tothe first monomer, second monomer and the cross-linking agent.

The copolymeric network in one method is soaked in a solvent (e.g.,water) to create a hydrogel composition. The solvent may include theabove discussed components such as electrolytes, enzymes, permeationenhancers, biocides, humectants, surfactants, and combinations thereof.It is contemplated that the electrolytes, enzymes, permeation enhancers,biocides, humectants, surfactants and combinations thereof may be addedseparately from the solvent to the copolymeric network.

In one method, the hydrogel composition is dried to remove the solventand form a dried copolymeric network or dried hydrogel composition. Thedried hydrogel composition may be in the form of film. The driedhydrogel composition may further include a mechanical support. Themechanical support assists in providing mechanical strength to the driedhydrogel composition film. Examples of mechanical supports includepolymeric mesh, woven fabric, non-woven fabric, cellulose (e.g., paper),or combinations thereof. Examples of cellulose materials includecommercially available paper (e.g., paper wipes, paper towels or filterpaper) or cellulosic cloth. It is contemplated that other mechanicalsupports may be used with the dried hydrogel composition film.

Generally, there is from about 10 to about 90 wt. % cellulose matrixwith the remainder being the copolymeric network. Thus, in oneembodiment, there is 10 wt. % cellulose matrix and 90 wt. % copolymericnetwork.

In one embodiment, the copolymeric network is absorbed into the porouscellulose matrix. For example, a graft co-polymerization reaction mayoccur between the first and second monomers onto a porous cellulosematrix. This reaction may be initiated by using high-energy radiation,chemical initiation and ultraviolet (UV) radiation in the presence ofphoto-initiators.

One example of a hydrogel composition is shown in FIG. 1 with a driedhydrogel film system 10 including a dried hydrogel composition film 12and a mechanical support 14. It is contemplated that the mechanicalsupport may be more than one layer. According to another embodiment, themechanical support may be embedded within the hydrogel composition.

In one process, the dried hydrogel composition film may be reconstitutedwith a solvent (e.g., water). The hydrogel composition, including thecopolymeric network and the solvent, may comprise from about 1 to about99 vol. % water.

In one method, the hydrogel composition is used to assist in determiningan analyte concentration of interstitial fluid (ISF) with a sensor. Morespecifically, the hydrogel composition is adapted to serve as aninterface generally between and coupling the skin and the sensor. Inthis method, the sensor determines the concentration of the desiredanalyte from a sampling of the ISF. In one embodiment, the sensor is anelectrochemical sensor. An example of an electrochemical sensor includesa standard, three-electrode potentiostat utilizing a catalytic,platinum-containing working electrode. It is contemplated that otherelectrochemical sensors may be used including those with fewerelectrodes such as a two electrode electrochemical sensor, whichincludes a counter electrode and a working electrode. It is alsocontemplated that other sensors may be used such as optical sensors.

Referring to FIG. 2, an electrochemical sensor is shown according to oneembodiment. An electrochemical sensor 30 includes a counter electrode32, a working electrode 34, and a reference electrode 36. One specificexample of such an electrochemical sensor includes a carbon counterelectrode, a platinum working electrode, and a silver/silver chloridereference electrode. It is contemplated that the counter, working andreference electrodes may be made of other materials.

As shown in FIG. 3, the electrochemical sensor system 50 includes theelectrochemical sensor 30 of FIG. 2, a dried hydrogel film 52 and anadhesive ring 54. The dried hydrogel film 52 includes a hydrogelcomposition such as those described above in the absence of a solvent.In this embodiment, the adhesive ring 54 has two functions: (a) to covera portion of the dried hydrogel film 52 and secure it to theelectrochemical sensor 30; and (b) to secure the electrochemical sensorsystem 50, including the dried hydrogel film 52, to the skin.

In one method, a hydrogel composition is added to the skin. The hydrogelcomposition may be located at a skin site such as the volar forearmbetween the wrist and elbow. It is contemplated that the hydrogelcomposition may be located at other skin sites such as the abdomen. Theskin is then pre-treated in this method to increase the skinpermeability. One example of pre-treating is to use ultrasound energy todisrupt the lipid bilayer of the stratum corneum so as to increase theskin permeability. By increasing the skin permeability, the amount ofinterstitial fluid (ISF) used in transdermal sampling is increased. Thisresults in improved sampling of the analytes of interest (e.g., glucose)found in the ISF. A sensor determines the concentration of the desiredanalyte after contacting the hydrogel composition and the ISF.

One non-limiting source of an ultrasound energy system is SontraSonoPrep® ultrasonic skin permeation system marketed by Sontra MedicalCorporation. The SonoPrep® system applies relatively low frequencyultrasonic energy to the skin for a limited duration (from about 10 to20 seconds). The ultrasonic horn contained in the device vibrates atabout 55,000 times per second (55 KHz) and applies energy to the skinthrough the liquid-coupling medium to create cavitation bubbles thatexpand and contract in the coupling medium.

In another method, a hydrogel composition is added to the skin from anelectrochemical sensor system (e.g., electrochemical sensor system 50).The skin is then pre-treated to increase the skin permeability. Oneexample of pre-treating is to use ultrasound energy as discussed aboveusing for, example, Sontra's SonoPrep® ultrasonic skin permeation systemmarketed by Sontra Medical Corporation. The electrochemical sensordetermines the concentration of the desired analyte after contacting thehydrogel composition and the ISF.

EXAMPLES Example 1

The glucose concentration was determined using non-invasive testing. Themethod for generating the plots shown in FIGS. 4a,b was as follows.

A copolymeric mixture included a first monomer (N-vinyl pyrrolidone), asecond monomer (vinyl acetate), a photo-initiator(2-Hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone) marketed asIrgacure® 2959 by Ciba Specialty Chemicals Pty Ltd., and a cross-linkingagent (diethylene glycol divinyl ether). The copolymeric mixtureincluded 50 parts N-vinyl pyrrolidone, 50 parts vinyl acetate, 0.5 partsIrgacure® 2959, and 0.5 parts diethylene glycol divinyl ether. The firstmonomer, second monomer, photo-initiator and cross-linking agent weremixed. The copolymeric mixture was bubbled with nitrogen (N₂) for about5 minutes. The copolymeric mixture was then placed under an ultravioletlamp for about 2.25 hours. The copolymeric mixture was then removed andstored in a refrigerator.

The copolymeric mixture was cured to form a dried copolymeric film. Thedried copolymeric film was purified by rinsing twice in hot deionizedwater at 80° C. for 2 hours. The copolymeric film was air cooled toreform the dried copolymeric film.

The dried copolymeric film was mixed with a solution at 4° C. for over16 hours to form a hydrogel film. The solution, which was previouslyprepared, was a phosphate-buffered saline solution that contained 5 wt.% glucose oxidase enzyme. The only other additive that was included inthis solution was a surfactant (0.05 wt. % Triton® X-100).

The hydrogel film was cut to the desired size and dried down on theworking area of an electrochemical sensor system. The dried hydrogelfilm on the electrochemical sensor was reconstituted with a bufferedsolvent (phosphate buffered saline) to form a hydrogel composition. Thehydrogel composition was applied to the volar forearm between the wristand the elbow at three different locations. Forearm Site 1 was closer tothe wrist, Forearm Site 3 was closer to the elbow, and Forearm Site 2was located between Forearm Sites 1 and 3.

The volar forearm skin at Forearm Sites 1-3 was pre-treated by applyingultrasound energy thereto. The glucose oxidase enzyme in the hydrogelcomposition contacted the skin and the interstitial fluid (ISF) thatcontained glucose. The glucose oxidase enzyme assisted in converting theglucose in the ISF into peroxide. In response to detecting the peroxide,electrical current from the electrochemical sensor was generated. Theelectrical current corresponds to the glucose concentration in the ISF.

The electrical current was measured for each of Forearm Sites 1-3 over aperiod of time. The actual glucose concentrations were also measuredover the same time period using a ANALOX—Glucose Analyser GM 10 marketedby Analis, which was the Comparative Method. This is labeled “PlasmaGlucose” in FIGS. 4a , 4 b.

Referring to FIG. 4a , the electrical current (in nano amps) determinedby the above method using Forearm Sites 1-3 and the Comparative Method(labeled Plasma Glucose in FIG. 4a ) were plotted versus time (inseconds). Additionally, the plot of FIG. 4a included glucose in mg/dL,which correlates to the measured electrical current. To better comparethe same, the readings of Forearm Sites 2 and 3 were normalized relativeto the highest observed sensor signal current. The normalized readingsof Forearm 2 and 3 are shown in FIG. 4b with Forearm Site 1 and thePlasma Glucose.

The results of the testing showed that the determined glucose valuesusing the inventive method (Forearm Sites 1-3) correlated with thesubject's parallel glucose values in a comparative method (PlasmaGlucose).

Example 2

In Example 2, two different inventive compositions were made. InInventive Hydrogel Pad 1, a copolymeric network and a cellulose matrixwere grafted together. In Inventive Hydrogel Pad 2, a copolymericnetwork was formed and then placed onto a nylon mesh.

Specifically, in Inventive Hydrogel Pad 1, a copolymeric network and acellulose matrix were grafted together. The copolymeric networkcomprised 60 parts of N-vinyl pyrrolidone (first monomer), 40 parts ofvinyl acetate (second monomer), 1 part of diethylene glycol divinylether, and 1 part of(2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiopheone, which is anultraviolet (UV) initiator. The weight ratio of the copolymeric networkto the cellulose matrix was 2:1. The cellulose matrix used was Kimwipes®absorbent wipers EX-L from Kimberly-Clark.

The monomer mixture was absorbed into the porous Kimwipes® absorbentwipers EX-L and then exposed to UV radiation for two hours to completethe polymerization reaction. After the reaction, the gelled copolymericnetwork and the cellulose matrix were immersed in water to removenon-reacted monomers. The cellulose interpenetrated the crosslinkedcopolymeric network and, thus, were chemically bonded together. Thefirst and second monomers were also chemically bonded to each other.

The chemically-bonded copolymeric/cellulose network were fully hydratedwith water to form a hydrogel sheet. After being fully hydrated, abuffer with an enzyme (glucose oxidase) was added to the hydrogel sheet.The hydrogel sheet was then dried and stored.

The hydrogel sheet was cut into a desired size to form a hydrogel pad.The hydrogel pad was attached to a surface of an electrochemical sensor.The attached hydrogel pad was then re-hydrated with water, whichincluded a buffer. Inventive Hydrogel Pad 1 was from about 60 to about90 wt. % water, and was generally uniform and mechanically stable.

The skin was treated with ultrasound energy using the Sontra SonoPrep®ultrasonic skin permeation system. Tests were performed on two differentareas of the skin—the wrist and elbow. Inventive Hydrogel Pad 1 wasadhered to the skin at each of these locations. The current was measuredby the electrochemical sensor and a glucose concentration was determinedat each location.

Inventive Hydrogel Pad 2 comprised a copolymeric network. Thecopolymeric network comprised 60 parts of N-vinyl pyrrolidone (firstmonomer), 40 parts of vinyl acetate (second monomer), 1 part ofdiethylene glycol divinyl ether, and 1 part of(2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiopheone. The copolymericnetwork was exposed to UV radiation for two hours to complete thepolymerization reaction. After the reaction, the gelled copolymericnetwork was immersed in water to remove non-reacted monomers. The firstand second monomers were chemically bonded to each other.

The copolymeric network was fully hydrated with water to form a hydrogelsheet. After being fully hydrated, a buffer with an enzyme (glucoseoxidase) was added to the hydrogel sheet. The hydrogel sheet was thendried and stored. To improve the handling of the hydrogel sheet, a nylonmesh was used to support the hydrogel sheet. The hydrogel sheet withnylon mesh was cut into a desired size to form Inventive Hydrogel Pad 2.Inventive Hydrogel Pad 2 was attached to a surface of an electrochemicalsensor. The attached Inventive Hydrogel Pad 2 was then re-hydrated withwater, which included a buffer. The hydrated Inventive Hydrogel Pad 2comprised from about 60 to about 90 wt. % water and was generallyuniform and mechanically stable.

The skin (forearm) was treated with ultrasound energy using the SontraSonoPrep® ultrasonic skin permeation system. The hydrated InventiveHydrogel Pad 2 was adhered to the skin (forearm). The current wasmeasured by the electrochemical sensor and a glucose concentration wasdetermined.

The results of the testing using Inventive Hydrogel Pads 1 and 2 areshown in FIG. 5. FIG. 5 plots current (nano amps) and glucoseconcentration (mg/dL) versus time. Specifically, FIG. 5 depicts theComparative Method (labeled Plasma Glucose in FIG. 5) that tested theblood and measured the glucose concentration using an electrochemicalsensor. The Comparative Method of FIG. 5 did not use a hydrogelcomposition. In the Comparative Method, blood samples were taken every30 minutes and analyzed with an Analox GM9D Analyzer, which is marketedby Analox Instruments U.S.A., Inc. of Lunenberg, Mass. The results ofthe methods using the Inventive Hydrogel Pad 1 (at both the wrist andelbow) and the Hydrogel Pad 2 (forearm) were also plotted. As shown inFIG. 5, the glucose concentrations from the inventive methods (usingInventive Hydrogel Pads 1 and 2) generally correlated with the subject'splasma glucose concentrations from Comparative Method 1.

Alternative Embodiment A

A hydrogel composition comprising a first monomer, a second monomer, across-linking agent, and a solvent, the first monomer being selectedfrom Formula I:

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed;

the second monomer being selected from the group consisting of FormulaII and Formula III, wherein Formula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents; and

wherein Formula III is

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein the ratio of the first monomer to the second monomer is fromabout 0.1:99.9 to about 99.9:0.1.

Alternative Embodiment B

The hydrogel composition of Alternative Embodiment A wherein thecross-linking agent is a multifunctional vinyl ether, a divinylbenzene,a multifunctional acrylate, or a multifunctional acrylamide.

Alternative Embodiment C

The hydrogel composition of Alternative Embodiment B wherein thecross-linking agent is a multifunctional vinyl ether, themultifunctional vinyl ether being a diethylene glycol divinyl etheracrylate, triethylene glycol divinyl ether, and tetra(ethylene glycol)divinyl ether.

Alternative Embodiment D

The hydrogel composition of Alternative Embodiment B wherein thecross-linking agent is a divinylbenzene.

Alternative Embodiment E

The hydrogel composition of Alternative Embodiment B wherein thecross-linking agent is a multifunctional acrylate, the multifunctionalacrylate being ethylene glycol dimethacrylate (EGDMA), polyethyleneglycol diacrylates, diethylene glycol dimethacrylate, diethylene glycoldiacrylate, ethylene glycol diacrylate, or1,3-dihydroxypropyldimethacrylate.

Alternative Embodiment F

The hydrogel composition of Alternative Embodiment B wherein thecross-linking agent is a multifunctional acrylamide.

Alternative Embodiment G

The hydrogel composition of Alternative Embodiment A wherein the solventis water.

Alternative Embodiment H

The hydrogel composition of Alternative Embodiment A further including aphoto-initiator.

Alternative Embodiment I

The hydrogel composition of Alternative Embodiment A wherein the ratioof the first monomer to the second monomer is from about 20:80 to about80:20.

Alternative Embodiment J

The hydrogel composition of Alternative Embodiment A wherein the secondmonomer is selected from Formula II.

Alternative Embodiment K

The hydrogel composition of Alternative Embodiment A wherein the secondmonomer is selected from Formula III.

Alternative Embodiment L

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaII with R3 or R4 being a (C₃-C₁₈)alkyl that is optionally substituted.

Alternative Embodiment M

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaII with R3 or R4 being a (C₃-C₇)cycloalkyl that is optionallysubstituted.

Alternative Embodiment N

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaII with R3 or R4 being an aromatic moiety that is optionallysubstituted.

Alternative Embodiment O

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaIII with R3 or R4 being a (C₃-C₁₈)alkyl that is optionally substituted.

Alternative Embodiment P

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaIII with R3 or R4 being a (C₃-C₇)cycloalkyl that is optionallysubstituted.

Alternative Embodiment Q

The hydrogel composition of Alternative Embodiment A wherein the firstmonomer is N-vinyl acetamide, N-vinyl propionamide, N-vinyl pyrrolidoneor N-vinyl caprolactam, the second monomer being selected from FormulaIII with R3 or R4 being an aromatic moiety that is optionallysubstituted.

Alternative Embodiment R

An electrochemical sensor system comprising:

an electrochemical sensor having at least a counter electrode and aworking electrode; and

a hydrogel composition contacting the working electrode, the hydrogelcomposition comprising a first monomer, a second monomer, across-linking agent, and a solvent, the first monomer being selectedfrom hydroxy alkyl methacrylates, acrylamide, N,N di-alkyl acrylamides,methacrylic acid, acrylic acid, methacrylate metal salts, acrylate metalsalts, iticonic acid, maleic acid, methacrylamide,N,N-dialkylacrylamide, styrene sulfonic acid, styrene sulfonate metalsalts, styrene carboxylic acid, styrene carboxylate metal salts,acrylamido-2-methylpropane sulfonic acid, acrylamido-2-methylpropanesulfonate metal salts, 2-vinyl N-alkylpyridinium halide, 4-vinylN-alkylpyridinium halide, or Formula I, wherein Formula I is

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed;

the second monomer being selected from the group consisting of alkyl(meth)acrylates, Formula II, Formula III, and Formula IV, whereinFormula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents; and

wherein Formula III is

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein Formula IV is

whereinR2 is selected from (C₁-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein the ratio of the first monomer to the second monomer is fromabout 0.1:99.9 to about 99.9:0.1.

Alternative Embodiment S

The electrochemical sensor system of Alternative Embodiment R furtherincluding an adhesive structure securing the hydrogel composition to theelectrochemical sensor.

Alternative Embodiment T

The electrochemical sensor system of Alternative Embodiment R whereinthe electrochemical sensor further includes a reference electrode.

Alternative Embodiment U

The electrochemical sensor system of Alternative Embodiment R whereinthe hydrogel composition is a dried hydrogel composition.

Alternative Embodiment V

The electrochemical sensor system of Alternative Embodiment U whereinthe dried hydrogel composition is a film.

Alternative Embodiment W

The electrochemical sensor system of Alternative Embodiment R furtherincluding a mechanical support to assist in providing mechanicalstrength to the hydrogel composition.

Alternative Embodiment X

The electrochemical sensor system of Alternative Embodiment W whereinthe mechanical support is polymeric mesh, woven fabric, non-wovenfabric, cellulose, or combinations thereof.

Alternative Embodiment Y

The electrochemical sensor system of Alternative Embodiment R whereinthe hydrogel composition has a thickness of from about 0.1 mil to about100 mils.

Alternative Embodiment Z

The electrochemical sensor system of Alternative Embodiment Y whereinthe hydrogel composition has a thickness of from about 1 mil to about 30mils.

Alternative Embodiment AA

The electrochemical sensor system of Alternative Embodiment R whereinthe ratio of the first monomer to the second monomer is from about 20:80to about 80:20.

Alternative Embodiment BB

An electrochemical sensor system comprising:

an electrochemical sensor having at least a counter electrode and aworking electrode; and

a hydrogel composition contacting the working electrode, the hydrogelcomposition comprising a first monomer, a second monomer, across-linking agent, and a solvent, the first monomer being selectedfrom Formula I

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed;

the second monomer being selected from the group consisting of alkyl(meth)acrylates, Formula II, Formula III, and Formula IV, whereinFormula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents; and

wherein Formula III is

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein Formula IV is

whereinR2 is selected from (C₁-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein the ratio of the first monomer to the second monomer is fromabout 0.1:99.9 to about 99.9:0.1.

Alternative Embodiment CC

The electrochemical sensor system of Alternative Embodiment BB furtherincluding an adhesive structure securing the hydrogel composition to theelectrochemical sensor.

Alternative Embodiment DD

The electrochemical sensor system of Alternative Embodiment BB whereinthe electrochemical sensor further includes a reference electrode.

Alternative Embodiment EE

The electrochemical sensor system of Alternative Embodiment BB whereinthe hydrogel composition is a dried hydrogel composition.

Alternative Embodiment FF

The electrochemical sensor system of Alternative Embodiment EE whereinthe dried hydrogel composition is a film.

Alternative Embodiment GG

The electrochemical sensor system of Alternative Embodiment BB furtherincluding a mechanical support to assist in providing mechanicalstrength to the hydrogel composition.

Alternative Embodiment HH

The electrochemical sensor system of Alternative Embodiment GG whereinthe mechanical support is polymeric mesh, woven fabric, non-wovenfabric, paper, or combinations thereof.

Alternative Embodiment II

The electrochemical sensor system of Alternative Embodiment BB whereinthe cross-linking agent is a multifunctional vinyl ether, adivinylbenzene, a multifunctional acrylate, or a multifunctionalacrylamide.

Alternative Embodiment JJ

The electrochemical sensor system of Alternative Embodiment BB whereinthe ratio of the first monomer to the second monomer is from about 20:80to about 80:20.

Alternative Embodiment KK

An electrochemical sensor system comprising:

an electrochemical sensor having at least a counter electrode and aworking electrode; and

a hydrogel composition contacting the working electrode, the hydrogelcomposition comprising a first monomer, a second monomer, across-linking agent, and a solvent, the first monomer being selectedfrom the group consisting of N-vinyl pyrrolidone, hydroxy alkylmethacrylates, acrylamide, and N,N di-alkyl acrylamides, the secondmonomer being selected from the group consisting of alkyl(meth)acrylates, N-vinyl acrylamide, vinyl esters, and vinyl ethers, andwherein the ratio of the first monomer to the second monomer is fromabout 0.1:99.9 to about 99.9:0.1.

Alternative Embodiment LL

The electrochemical sensor system of Alternative Embodiment KK furtherincluding an adhesive structure securing the hydrogel composition to theelectrochemical sensor.

Alternative Embodiment MM

The electrochemical sensor system of Alternative Embodiment KK whereinthe electrochemical sensor further includes a reference electrode.

Alternative Embodiment NN

The electrochemical sensor system of Alternative Embodiment KK whereinthe hydrogel composition is a dried hydrogel composition.

Alternative Embodiment OO

The electrochemical sensor system of Alternative Embodiment NN whereinthe dried hydrogel composition is a film.

Alternative Embodiment PP

The electrochemical sensor system of Alternative Embodiment KK furtherincluding a mechanical support to assist in providing mechanicalstrength to the hydrogel composition.

Alternative Embodiment QQ

The electrochemical sensor system of Alternative Embodiment PP whereinthe mechanical support is polymeric mesh, woven fabric, non-wovenfabric, paper, or combinations thereof.

Alternative Embodiment RR

The electrochemical sensor system of Alternative Embodiment KK whereinthe first monomer is N-vinyl pyrrolidone and the second monomer is avinyl ester.

Alternative Embodiment SS

The electrochemical sensor system of Alternative Embodiment KK whereinthe cross-linking agent is a multifunctional vinyl ether, adivinylbenzene, a multifunctional acrylate, or a multifunctionalacrylamide.

Alternative Embodiment TT

The electrochemical sensor system of Alternative Embodiment KK whereinthe ratio of the first monomer to the second monomer is from about 20:80to about 80:20.

Alternative Embodiment UU

An electrochemical sensor system comprising:

an electrochemical sensor having at least a counter electrode and aworking electrode; and

a hydrogel composition contacting the working electrode, the hydrogelcomposition comprising a first monomer, a second monomer, across-linking agent, and a solvent, the first monomer having hydrophiliccharacteristics, the second monomer having hydrophobic characteristics,and wherein the ratio of the first monomer to the second monomer is fromabout 0.1:99.9 to about 99.9:0.1.

Alternative Process A

A method of determining an analyte concentration, the method comprisingthe acts of:

placing a hydrogel composition on skin, the hydrogel compositioncomprising a first monomer, a second monomer, a cross-linking agent, anda solvent, the first monomer being selected from hydroxy alkylmethacrylates, acrylamide, N,N di-alkyl acrylamides, methacrylic acid,acrylic acid, methacrylate metal salts, acrylate metal salts, iticonicacid, maleic acid, methacrylamide, N,N-dialkylacrylamide, styrenesulfonic acid, styrene sulfonate metal salts, styrene carboxylic acid,styrene carboxylate metal salts, acrylamido-2-methylpropane sulfonicacid, acrylamido-2-methylpropane sulfonate metal salts, 2-vinylN-alkylpyridinium halide, 4-vinyl N-alkylpyridinium halide, or FormulaI, wherein Formula I is

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed;

the second monomer being selected from the group consisting of alkyl(meth)acrylates, Formula II, Formula III, and Formula IV, whereinFormula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents; and

wherein Formula III is

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein Formula IV is

whereinR2 is selected from (C₁-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos, wherein the ratio of thefirst monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1;

providing a sensor, the hydrogel composition located generally betweenand coupling the skin and the sensor; and

sampling of the interstitial fluid to determine the analyteconcentration using the sensor.

Alternative Process B

The method of Alternative Process A further including pre-treating theskin to improve permeability of the skin.

Alternative Process C

The method of Alternative Process B wherein the pre-treating includesapplying ultrasound energy to the skin.

Alternative Process D

The method of Alternative Process A wherein the skin is the volarforearm.

Alternative Process E

The method of Alternative Process A wherein the analyte is glucose.

Alternative Process F

The method of Alternative Process A wherein the sensor is anelectrochemical sensor.

Alternative Process G

The method of Alternative Process A wherein the ratio of the firstmonomer to the second monomer is from about 20:80 to about 80:20.

Alternative Process H

A method of determining an analyte concentration, the method comprisingthe acts of:

placing a hydrogel composition on skin, the hydrogel compositioncomprising a first monomer, a second monomer, a cross-linking agent, anda solvent, the first monomer being selected from Formula I

whereinR and R1 are independently selected from H, (C₁-C₃)alkyl,(C₃-C₆)dihydroxy alkyl and (C₂-C₆)hydroxy alkyl; or

the combination of R and R1 is selected from 1 carbon to 5 carbon atomssuch that a 3-7 member heterocyclic moiety is formed;

the second monomer being selected from the group consisting of alkyl(meth)acrylates, Formula II, Formula III, and Formula IV, whereinFormula II is

whereinR3 and R4 are independently selected from H, CH₃, (C₃-C₁₈)alkyl, whereinthe alkyl is optionally substituted with one or more substituentsselected from halos, haloalkyls, cycloalkyls, nitros, cyanos, 4-8 memberheterocyclic moieties, wherein the heterocyclic moieties are optionallysubstituted with one or more alkyls, halos, haloalkyls, cycloalkyls,nitros, and cyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

with the proviso that when R3 is H or CH₃, then R4 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents,

with the proviso that when R4 is H or CH₃, then R3 is (C₃-C₁₈)alkyl,(C₃-C₇)cycloalkyl or an aromatic moiety, wherein the alkyl, cycloalkylor aromatic moiety is optionally substituted with one or moresubstituents; and

wherein Formula III is

whereinR5 is selected from (C₃-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos,

wherein Formula IV is

whereinR2 is selected from (C₁-C₁₈)alkyl, wherein the alkyl is optionallysubstituted with one or more substituents selected from halos,haloalkyls, cycloalkyls, nitros, cyanos, 4-8 member heterocyclicmoieties, wherein the heterocyclic moieties are optionally substitutedwith one or more alkyls, halos, haloalkyls, cycloalkyls, nitros, andcyanos;

(C₃-C₇)cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more substituents selected from alkyls, halos, haloalkyls,cycloalkyls, nitros, and cyanos; and

aromatic moieties, wherein the aromatic moieties are optionallysubstituted with one or more substituents selected from alkyls, halos,haloalkyls, cycloalkyls, nitros, and cyanos, wherein the ratio of thefirst monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1;

providing a sensor, the hydrogel composition located generally betweenand coupling the skin and the sensor; and

sampling of the interstitial fluid to determine the analyteconcentration using the sensor.

Alternative Process I

The method of Alternative Process H further including pre-treating theskin to improve permeability of the skin.

Alternative Process J

The method of Alternative Process I wherein the pre-treating includesapplying ultrasound energy to the skin.

Alternative Process K

The method of Alternative Process H wherein the skin is the volarforearm.

Alternative Process L

The method of Alternative Process H wherein the analyte is glucose.

Alternative Process M

The method of Alternative Process H wherein the sensor is anelectrochemical sensor.

Alternative Process N

The method of Alternative Process H wherein the ratio of the firstmonomer to the second monomer is from about 20:80 to about 80:20.

Alternative Process O

A method of determining an analyte concentration, the method comprisingthe acts of:

placing a hydrogel composition on skin, the hydrogel compositioncomprising a first monomer, a second monomer, a cross-linking agent, anda solvent, the first monomer being selected from the group consisting ofN-vinyl pyrrolidone, hydroxy alkyl methacrylates, acrylamide, and N,Ndi-alkyl acrylamides, the second monomer being selected from the groupconsisting of alkyl (meth)acrylates, N-vinyl acylamide, vinyl esters,and vinyl ethers, and wherein the ratio of the first monomer to thesecond monomer is from about 0.1:99.9 to about 99.9:0.1;

providing a sensor, the hydrogel composition located generally betweenand coupling the skin and the sensor; and

sampling of the interstitial fluid to determine the analyteconcentration using the sensor.

Alternative Process P

The method of Alternative Process O further including pre-treating theskin to improve permeability of the skin.

Alternative Process Q

The method of Alternative Process P wherein the pre-treating includesapplying ultrasound energy to the skin.

Alternative Process R

The method of Alternative Process O wherein the skin is the volarforearm.

Alternative Process S

The method of Alternative Process O wherein the analyte is glucose.

Alternative Process T

The method of Alternative Process O wherein the sensor is anelectrochemical sensor.

Alternative Process U

The method of Alternative Process O wherein the first monomer is N-vinylpyrrolidone and the second monomer is a vinyl ester.

Alternative Process V

The method of Alternative Process U wherein the cross-linking agent is amultifunctional vinyl ether, a divinylbenzene, a multifunctionalacrylate, or a multifunctional acrylamide.

Alternative Process W

The method of Alternative Process O wherein the ratio of the firstmonomer to the second monomer is from about 20:80 to about 80:20.

Alternative Process X

A method of determining an analyte concentration, the method comprisingthe acts of:

placing a hydrogel composition on skin, the hydrogel compositioncomprising a first monomer, a second monomer, a cross-linking agent, anda solvent, the first monomer having hydrophilic characteristics, thesecond monomer having hydrophobic characteristics, wherein the ratio ofthe first monomer to the second monomer is from about 0.1:99.9 to about99.9:0.1;

providing a sensor, the hydrogel composition located generally betweenand coupling the skin and the sensor; and

sampling of the interstitial fluid to determine the analyteconcentration using the sensor.

While the present invention has been described with reference to one ormore particular embodiments, those skilled in the art will recognizethat many changes may be made thereto without departing from the spiritand scope of the present invention. Each of these embodiments, andobvious variations thereof, is contemplated as falling within the spiritand scope of the invention.

The invention claimed is:
 1. An electrochemical sensor systemcomprising: an electrochemical sensor having at least a counterelectrode and a working electrode; and a hydrogel composition contactingthe working electrode, the hydrogel composition comprising a firstmonomer, a second monomer, a cross-linking agent, and a solvent, thefirst monomer being selected from Formula I, wherein Formula I is

wherein the combination of R and R1 is selected from 1 carbon to 5carbon atoms such that a 3-7 member heterocyclic moiety is formed; thesecond monomer being selected from the group consisting of Formula IIIwherein Formula III is

wherein R5 is selected from (C₃-C₇)cycloalkyl, wherein the cycloalkyl isoptionally substituted with one or more substituents selected fromalkyls, halos, haloalkyls, cycloalkyls, nitros, and cyanos; and whereinthe ratio of the first monomer to the second monomer is from about 20:80to about 80:20.
 2. The electrochemical sensor system of claim 1, furtherincluding a mechanical support to assist in providing mechanicalstrength to the hydrogel composition.
 3. The electrochemical sensorsystem of claim 2, wherein the mechanical support is polymeric mesh,woven fabric, non-woven fabric, cellulose, or combinations thereof. 4.The electrochemical sensor system of claim 1, wherein the hydrogelcomposition has a thickness of from about 0.1 mil to about 100 mils. 5.The electrochemical sensor system of claim 4, wherein the hydrogelcomposition has a thickness of from about 1 mil to about 30 mils.
 6. Theelectrochemical sensor system of claim 1, wherein the ratio of the firstmonomer to the second monomer is from about 40:60 to about 60:40.
 7. Theelectrochemical sensor system of claim 1, wherein the first monomer isN-vinyl pyrrolidone or N-vinyl caprolactam, the second monomer beingselected from Formula III with R5 being a (C₃-C₇)cycloalkyl that isoptionally substituted.
 8. A method of determining an analyteconcentration, the method comprising the acts of: placing a hydrogelcomposition on skin, the hydrogel composition comprising a firstmonomer, a second monomer, a cross-linking agent, and a solvent, thefirst monomer being selected from Formula I, wherein Formula I is

wherein the combination of R and R1 is selected from 1 carbon to 5carbon atoms such that a 3-7 member heterocyclic moiety is formed; thesecond monomer being selected from the group consisting of Formula III,wherein Formula III is

wherein R5 is selected from (C₃-C₇)cycloalkyl, wherein the cycloalkyl isoptionally substituted with one or more substituents selected fromalkyls, halos, haloalkyls, cycloalkyls, nitros, and cyanos; and whereinthe ratio of the first monomer to the second monomer is from about 20:80to about 80:20; providing a sensor, the hydrogel composition locatedgenerally between and coupling the skin and the sensor; and sampling ofthe interstitial fluid to determine the analyte concentration using thesensor.
 9. The method of claim 8, wherein the analyte is glucose. 10.The method of claim 8, wherein the sensor is an electrochemical sensor.11. The method of claim 8, wherein the ratio of the first monomer to thesecond monomer is from about 40:60 to about 60:40.
 12. The method ofclaim 8, wherein the first monomer is N-vinyl pyrrolidone or N-vinylcaprolactam, the second monomer being selected from Formula III with R5being a (C₃-C₇)cycloalkyl that is optionally substituted.